The present invention relates to apparatus and methods for perfusing myocardial tissue and stimulating tissue growth and revascularization in a vessel or organ. More particularly, the present invention relates to a device that may be implanted in a vessel or organ, such as the heart, to form a channel for perfusing tissue, and may include a bioactive agent to stimulate tissue regeneration and vascularization.
A leading cause of death in the United States and the world today is coronary artery disease, in which atherosclerotic plaque causes blockages in the coronary arteries, resulting in ischemia of the heart (i.e., inadequate blood flow to the myocardium). The disease manifests itself as chest pain or angina. In 1996, approximately 7 million people suffered from angina in the United States.
Coronary artery bypass grafting (CABG), in which the patient""s chest is surgically opened and an obstructed artery replaced with a native artery harvested elsewhere or a synthetic graft, has been the conventional treatment for coronary artery disease for the last thirty years. Such surgery creates significant trauma to the patient, requires long recuperation time, and poses serious risks of mortality. In addition, experience has shown that the bypass vessel or graft becomes obstructed with time, requiring further surgery.
More recently, catheter-based therapies such as percutaneous transluminal coronary angioplasty (PTCA) and atherectomy have been developed. In PTCA, a mechanical dilatation device is disposed across an obstruction in the patient""s artery and then dilated to compress the plaque lining the artery to restore patency to the vessel. Atherectomy involves using a catheter having a mechanical cutting tip or a laser to cut (or ablate) a passage through the blockage. Such methods have drawbacks, however, ranging from re-blockage of vessels dilated by angioplasty, to catastrophic rupture or dissection of the vessel during atherectomy. Moreover, these methods only may be used for that fraction of the patient population that have a few, easily accessible blockages. Neither technique is suitable for the treatment of diffuse atherosclerosis.
A more recent experimental technique for treating ischemia uses recombinant protein therapy to induce neoangiogenesis in the human heart. Schumacher et al., Induction of Neoangiogenesis in Ischemic Myocardium by Human Growth Factors, 97 Circulation 645 (1998) report the results of a study in which fibroblast growth factor (FGF-I), a human growth factor obtained through genetic engineering, was injected into the myocardium of 20 patients suffering from stenosis of the internal mammary artery/left anterior descending coronary artery. Within 4 days after application of FGF-I, new capillary vessels radiated outward from the injection point. Although the results of the study appear encouraging, it is unclear whether growth factor therapy alone will be able to treat occlusions of the greater coronary vessels.
Another recent technique that holds promise of treating a large percentage of the patient population, including those patients suffering from diffuse atherosclerosis, is referred to as transmyocardial revascularization (TMR). In this method, a series of channels are formed in the left ventricular wall of the heart. The channels may be transmural (i.e., from the epicardium to the endocardium), or intramural (for example, from the endocardium and terminating in the myocardium).
Typically, between 15 and 40 channels about 1 mm in diameter and up to 3.0 cm deep are formed with a laser in the wall of the left ventricle to perfuse the heart muscle with blood coming directly from the inside of the left ventricle, rather than from the coronary arteries. Apparatus and methods have been proposed to create these channels both percutaneously and intraoperatively (i.e., with the chest opened).
U.S. Pat. Nos. 5,380,316 and 5,554,152 to Aita et al. describe intraoperative laser apparatus for forming channels extending from the epicardium to the endocardium. The laser includes an optical wave guide that is held against the patient""s heart. Several pulses of the laser are required to form a transmural channel by ablation. U.S. Pat. No. 5,389,096 to Aita et al. describes a catheter-based laser system for performing TMR percutaneously, i.e., from within the left ventricle. U.S. Pat. No. 4,658,817 to Hardy describes a laser-based system for intraoperatively performing TMR that includes a needle portion for perforating an outer portion of the tissue, and a laser for ablating the inner portion.
U.S. Pat. No. 5,591,159 to Taheri describes a mechanical catheter-based apparatus for performing TMR involving a catheter having an end effector formed from a plurality of spring-loaded needles. The catheter first is positioned percutaneously within the left ventricle. Then, a plunger is released so that the needles are thrust into the endocardium, and the needles are withdrawn, thus forming small channels that extend into the myocardium. The patent suggests that the needles may be withdrawn and advanced repeatedly at different locations under fluoroscopic guidance.
Although TMR has been observed to benefit many patients, researchers do not agree upon the mechanism by which TMR provides therapeutic benefits. One theory proposes that TMR channels remain patent for long periods of time, and provide a path by which oxygenated blood perfuses the myocardium. Relatively recent histological studies, however, indicate that TMR channels may close within a short time following the procedure. Fleischer et al., One-Month Histologic Response Of Transmyocardial Laser Channels With Molecular Intervention, 62 Ann. Soc. Thoracic Surg. 1051-58 (1996), describe a study that evaluated the histologic changes associated with laser TMR in a 1-month nonischemic porcine model, and report that the researchers were unable to demonstrate channel patency 28 days after TMR.
Patent Cooperation Treaty Publication No. WO 97/32551 describes apparatus for performing TMR that creates a TMR channel and then implants a stent in the channel to maintain channel patency. For intraoperative TMR, a needle obturator first creates a channel in the myocardium, and a stent is then inserted in the channel. For percutaneous TMR, a drill at the end of a catheter first forms channels in the myocardium, and then a stent is inserted into the channel.
The foregoing apparatus have the disadvantage of requiring separate needle obturators or drills that must first create the channel before the stent is inserted into the myocardium. It therefore would be desirable to provide TMR stent apparatus to maintain channel patency, but that does not require a separate channel forming device.
An alternative theory regarding the means by which TMR provides therapeutic benefits proposes that in addition to channel formation and patency, myocardial neovascularization outside the channel area following channel formation is also important. To investigate this theory, researchers have combined the techniques of TMR and neoangiogenesis to study the use of gene therapy to promote blood vessel growth in the tissue surrounding laser TMR channels. In one study, researchers intraoperatively administered a single dose of vascular endothelial growth factor (VEGF) within the channels formed by laser TMR. While no significant increase in myocardial vascularity was observed, it was hypothesized that increased residency of VEGF may be required to stimulate angiogenesis.
Because the therapeutic benefit of TMR may result from a combination of channel patency and myocardial angiogenesis outside the channel area, it also would be desirable to provide methods and apparatus that maintain TMR channel patency and stimulate neoangiogenesis in the myocardial tissue surrounding TMR channels.
In view of the foregoing, it is an object of this invention to provide apparatus and methods for simultaneously forming a channel within a vessel or organ and introducing a stent to retain that channel patent, without requiring the use of a separate channel forming device.
It is a further object of the present invention to provide apparatus and methods comprising an implantable device that maintains channel patency and that may include a bioactive agent to stimulate tissue growth and revascularization.
It is a further object of this invention to provide apparatus and methods for implanting a series of stents at a plurality of tissue locations without having to repeatedly reload the stent delivery system.
These and other objects of the present invention are accomplished by providing a stent that simultaneously creates a channel in a vessel or organ and becomes implanted therein, to maintain the patency of the channel. The stent preferably includes a first end region that forms an intramural channel, and means for retaining the stent within the channel, such as an expandable mesh portion, barbs, tines or ribs, so that it is not dislodged by heart wall motion. The stent may comprise a bioactive agent to stimulate tissue regeneration and/or vascularization in tissue adjacent to the stent following implantation.
In one embodiment, the stent is configured from implantation in the left ventricle to promote perfusion and angiogenesis. The stent preferably includes a bore having an inlet, an outlet, and a plurality of apertures that extend from the bore to an exterior lateral surface of the stent. The stent may be fabricated from a bioresorbable material impregnated with a bioactive agent, such as an angiogenic growth factor, or alternatively, from nonresorbable material coated with a layer of a bioactive agent.
The stent optionally may include a second end region having means for securing the stent against movement, such as a flange, or one or more self-expanding barbs or tines. In other embodiments the stent may comprise a series of conical ribs or conical sections formed of a bioresorbable material impregnated with a bioactive agent, or may include bioactive agents that vary as a function of length or thickness of the stent. In yet other embodiments, the stent may comprise a rod of bioresorbable material that is implanted intraoperatively adjacent to a constricted artery to stimulate revascularization.
Delivery systems and methods of use are also provided for simultaneously forming a channel in a vessel or organ, and implanting the stent.